Compositions and methods for altering second messenger signaling

Abstract

The present disclosure provides, among other things, compounds comprising cyclic dinucleotides containing a 2',5' linkage useful in the design of research tools, as research tools, and as therapeutic modalities such as enzyme modulators.

We claim: 
     
       1. A compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         Ring A is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         Ring B is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         each X 1  and X 2  is independently —CR— or —N—; 
         X 3  is —C(R) 2 —, —O—, or —NR—; 
         X a  and X b  are independently —C(R) 2 —, —C(R)═C(R)—, —O—, —S—, —S(O)—, —S(O) 2 —, or —N(R)—; 
         X a1  and X b1  are —C(R)—; 
         X c  and X d  are independently oxygen, sulfur, a substituted nitrogen atom, BH 3 , or optionally substituted C 1-12  aliphatic, provided at least one of X c  and X d  is sulfur, a substituted nitrogen atom, BH 3 , or optionally substituted C 1-12  aliphatic; 
         each X c  and X f  is independently —O—, —S—, or —N(R)—; 
         each W is P; 
         each R 1  and R 2  is independently selected from the group consisting of hydrogen, halogen, —NO 2 , —CN, —OR a , —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 ,—N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , and optionally substituted C 1-12  aliphatic or C 1-4  alkoxy-C 1-4  alkyl; 
         each R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , and R 11  is independently selected from the group consisting of hydrogen, halogen, —NO 2 , —CN, —OR, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , or an optionally substituted group selected from C 1-12  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated monocyclic carbocyclic ring, a 7-10 membered saturated or partially unsaturated bicyclic carbocyclic ring, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; 
         each R 8  and R 9 , when present, is independently selected from the group consisting of hydrogen, halogen, —NO 2 , —CN, —OR′, —SR, —N(R) 2 , —C(O)R, —CO 2 R, —C(O)C(O)R, —C(O)CH 2 C(O)R, —S(O)R, —S(O) 2 R, —C(O)N(R) 2 , —SO 2 N(R) 2 , —OC(O)R, —N(R)C(O)R, —N(R)N(R) 2 , —N(R)C(═NR)N(R) 2 , —C(═NR)N(R) 2 , —C═NOR, —N(R)C(O)N(R) 2 , —N(R)SO 2 N(R) 2 , —N(R)SO 2 R, —OC(O)N(R) 2 , and optionally substituted C 1-12  aliphatic; 
         each R is independently selected from the group consisting of hydrogen or an optionally substituted group selected from C 1-6  aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, a 3-7 membered saturated or partially unsaturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and a 5-6 membered heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or: 
         two R groups on the same nitrogen are taken together with their intervening atoms to form an optionally substituted 3-7 membered saturated, partially unsaturated, or heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and 
         R a  is an oxygen protecting group or R, 
         wherein each optionally substituted group is:
 independently optionally substituted on a substitutable carbon atom with one or more of halogen, C 1-6  alkyl, —OR o , —SR o , or —N(R o ) 2 , wherein each R o  is independently hydrogen or C 1-6  alkyl; or 
 independently optionally substituted on a substitutable nitrogen atom with one or more of C 1-6  alkyl, —C(O)R † , —C(O)OR † , —S(O) 2 R † , or —S(O) 2 NR †   2 , wherein each R † is independently hydrogen or C 1-6  alkyl. 
 
       
     
     
       2. The compound of  claim 1 , wherein Ring A is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
       3. The compound of  claim 2 , wherein R 1  and R 2  are each independently selected from the group consisting of hydrogen, halogen, —OR a , or —NH 2 . 
     
     
       4. The compound of  claim 3 , wherein each R 3 , R 5 , and R 7  is independently selected from the group consisting of hydrogen and halogen, and wherein each R 4  and R 6  is independently selected from the group consisting of hydrogen, halogen, and —NH 2 . 
     
     
       5. The compound of  claim 4 , wherein each X 1  is —N—, each X 2  is —N—, and each X 3  is —NH—. 
     
     
       6. The compound of  claim 5 , wherein each X c  and X f  is —O—; X a  and X b  are —O—; and X a1  and X b1  are —CH—. 
     
     
       7. The compound of  claim 6 , wherein R 10  and R 11  are hydrogen, and wherein the subindex of the carbon atoms to which each R 8  and R 9  is attached is 0. 
     
     
       8. The compound of  claim 7 , wherein R a  is R, and each R is hydrogen. 
     
     
       9. The compound of  claim 8 , wherein one of X c  and X d  is sulfur. 
     
     
       10. The compound of  claim 9 , wherein one of X c  and X d  is sulfur, and the other of X c  and X d  is oxygen or sulfur. 
     
     
       11. The compound of  claim 10 , wherein X c  and X d  are both sulfur. 
     
     
       12. The compound of  claim 1 , wherein:
 Ring A is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         X 3  is —C(R) 2 —or —NR—; 
         X a  and X b  are independently —C(R) 2 —, —O—, —S—, —S(O)—, or —S(O) 2 —; 
         X c  and X d  are independently oxygen, sulfur, a substituted nitrogen atom, BH 3 , or optionally substituted C 1-12  aliphatic, provided at least one of X c  and X d  is sulfur, a substituted nitrogen atom, or BH 3 ; 
         each R 1  and R 2  is independently selected from the group consisting of hydrogen, halogen, —CN, 
         —OR a , —N(R) 2 , —OC(O)R, —OC(O)N(R) 2 , and optionally substituted C 1-12  aliphatic; 
         each R 3 , R 4 , R 5 , R 6 , R 7 , R 10  and R 11  is independently selected from the group consisting of hydrogen, halogen, —CN, —OR, —SR, —N(R) 2 , —C(O)R, —C(O)N(R) 2 , —N(R)C(O)R, and optionally substituted C 1-12  aliphatic; 
         each R is independently selected from the group consisting of hydrogen, optionally substituted C 1-6  aliphatic, and optionally substituted phenyl; and 
         the subindex of the carbon atoms to which each R 8  and R 9  is attached is 0. 
       
     
     
       13. The compound of  claim 12 , wherein each optionally substituted group of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 10 , R 11  and R is independently optionally substituted with one or more of halogen, C 1-6  alkyl, —OR o , —SR o , or —N(R o ) 2 , wherein each R o  is independently hydrogen or C 1-6  alkyl. 
     
     
       14. The compound of  claim 13 , wherein:
 each X 1  and X 2  is independently —CR— or —N—, wherein each R is independently hydrogen or C 1-6  aliphatic; 
 X 3  is —NH—; 
 X a  and X b  are independently —O— or —S—; 
 X a1  and X b1  are independently —CH—; 
 each X c  and X f  is independently —O—, —S—, or —NH—; 
 each R 1  and R 2  is independently selected from the group consisting of hydrogen, halogen, —CN, —OR a , —N(R) 2  wherein each R is independently hydrogen or C 1-6  aliphatic, and C 1-12  aliphatic optionally substituted with one or more of halogen, —OR o , and —N(R o ) 2 ; 
 each R 3 , R 4 , R 5 , R 6 , and R 7  is independently selected from the group consisting of hydrogen, halogen, —CN, —OR wherein R is hydrogen or C 1-6  aliphatic, —SR wherein R is hydrogen or C 1-6  aliphatic, —N(R) 2  wherein each R is independently hydrogen or C 1-6  aliphatic, —C(O)N(R) 2  wherein each R is independently hydrogen or C 1-6  aliphatic, —N(H)C(O)R wherein R is hydrogen, C 1-6  aliphatic, or phenyl, and C 1-12  aliphatic optionally substituted with one or more of halogen, —OR o , and —N(R o ) 2 ; 
 each R 10  and R 11  is independently hydrogen or C 1-2  alkyl; 
 R a  is an oxygen protecting group, hydrogen, or C 1-6  aliphatic; and 
 each R o  is independently hydrogen or C 1-6  aliphatic. 
 
     
     
       15. The compound of  claim 14 , wherein:
 each X 1  and X 2  is independently —CH— or —N—; 
 one of X c  and X d  is sulfur, and the other of X c  and X d  is oxygen or sulfur; 
 each X c  and X f  is —O—; 
 each R 1  and R 2  is independently selected from the group consisting of hydrogen, halogen, —OR a , and —NH 2 ; 
 each R 3 , R 4 , R 5 , R 6 , and R 7  is independently selected from the group consisting of hydrogen, halogen, —OR wherein R is hydrogen or C 1-6  alkyl, —SR wherein R is hydrogen or C 1-6  alkyl, 
 —NH 2 , and —N(H)C(O)R wherein R is hydrogen, C 1-6  alkyl, or phenyl; and 
 R a  is an oxygen protecting group or hydrogen. 
 
     
     
       16. The compound of  claim 1 , wherein the compound is of formula II-a: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       17. The compound of  claim 16 , wherein the compound is of formula X, XIV, or XVI: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       18. The compound of  claim 16 , wherein:
 Ring A is 
 
       
         
           
           
               
               
           
         
         each X 1  is —N—; 
         each R 3  and R 5  are hydrogen; 
         each R 4  is —NH 2 ; 
         X a  and X b  are —O—; 
         X c  and X f  are —O—; 
         R 1  and R 2  are —OH; 
         X a1  and X b1  are —CH—; 
         R 10  and R 11  are hydrogen; and 
         R 8  and R 9  are hydrogen; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       19. The compound of  claim 16 , wherein:
 Ring A is 
 
       
         
           
           
               
               
           
         
         each X 1  is —N—; 
         each R 3  and R 5  are hydrogen; 
         each R 4  is —NH 2 ; 
         X a  and X b  are —O—; 
         X c  and X d  are sulfur; 
         X c  and X f  are —O—; 
         R 1  and R 2  are —OH; 
         X a1  and X b1  are —CH—; 
         R 10  and R 11  are hydrogen; and 
         the subindex of the carbon atoms to which each R 8  and R 9  is attached is 0; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       20. A pharmaceutical composition comprising the compound  claim 1  and a pharmaceutically acceptable carrier.